The primary objective of this project is to determine the mechanism by which TSH regulates thyroid gland function. TSH rapidly stimulates the adenylate cyclase-cyclic AMP system and most, if not all, of the metabolic effects of TSH can be reproduced by the cyclic nucleotides. Since the initial step in TSH action is binding of the hormone to receptor sites on the plasma membrane, studies utilizing such membrane preparations containing a TSH responsive adenylate cyclase will be done. The binding of I131 TSH to such plasma membranes will be characterized and the role of phospholipids in such binding and action of TSH investigated. Other substances, such as long-acting thyroid stimulator (LATS), prostaglandins and cholera enterotoxin, mimic many of the effects of TSH and their binding to plasma membranes and interaction with TSH binding will also be investigated. Since cyclic AMP probably exerts its effect by activating protein kinases, attempts will be made to elucidate this process and its relationships to increased glucose oxidation and phospholipid synthesis. Further studies will be done to understand the failure of "cold" thyroid nodules to concentrate I131 and respond to TSH in vivo.